U.S. Pat. Nos. 5,703,079 and 5,661,151 (see Column 69, ex. 24) disclose posaconazole, a broad spectrum anti-fungal agent, the structure of which is illustrated below:
U.S. Pat. No. 6,958,337 discloses crystalline forms of posaconazole. United States Patent Application 20060160823 describes a formulation consisting of an injectable suspension. A solid (capsule/tablet) of posaconazole is disclosed in U.S. Pat. Nos. 5,972,381 and 5,834,472.
Posaconazole is marketed as an oral suspension (40 mg/ml) under the trademark NOXAFIL™ in the United States by Merck (formerly Schering Corporation, Kenilworth, N.J.). NOXAFIL™ (posaconazole) is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy. NOXAFIL™ (posaconazole) is also indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.
Posaconazole is a weakly basic and poorly-aqueous soluble drug that has poor bioavailability and variable absorption. Posaconazole has a solubility of less than 1 μg/mL in neutral and basic aqueous solutions. Although the solubility increases under acidic conditions (e.g., 3 μg/mL at pH 3 and 0.8 mg/mL at pH 1), a more dramatic increase in solubility would be required to meet the projected daily intravenous dosage of more than 100 mg.
Thus, it would be advantageous to have available to patients an intravenous solution formulation to boost the bioavailability of posaconazole. An injectable formulation would also allow administration to patients that cannot be given oral dosage forms, such as in the case of patients who have difficulty swallowing or who are unconscious. Of course, any such intravenous formulation would have to display chemical and physical stability over the shelf life of the product.